Camptothecin is a cytotoxin that inhibits topoisomerase I, an enzyme essential for DNA synthesis, and was first isolated from the leaves of the Camptotheca acuminata tree. Camptothecin showed anti-cancer activity in clinical trials but was poorly soluble and generated adverse drug reactions. Topotecan (Hycamtin, GlaxoSmithKline) and irinotecan (Campto, Yakult Honsha, and Camptosar, Pfizer) are semisynthetic derivatives of camptothecin, with the former approved by the U.S. FDA for the treatment of ovarian, cervical, and small cell lung cancer, and the latter approved for the treatment of colon cancer. Irinotecan is activated by hydrolysis to SN-38. The structures of these compounds are shown below along with the numbering used herein for the camptothecin ring.
Camptothecin: R1a=R1b=R2=H;Topotecan: R1a=—CH2NMe2, R1b=OH, and R2=H;Irinotecan: R1a=H, R1b=
and R2=Et; andSN-38: R1a=H, R1b=OH, R2=Et.
The camptothecin derivatives approved for anti-cancer use are susceptible to one or more of the several mechanisms by which cancer cells can become resistant to chemotherapy. There remains a need for new camptothecin derivatives, particularly derivatives that are more potent anti-cancer agents, can be used to treat cancers resistant to treatment with the approved derivatives, and/or exhibit fewer or less severe adverse side effects. The present invention meets this need.